PGI.sub.2 (prostacyclin) is one of the substances synthesized by arachidonic acid cascade and is confirmed to have many physiological actions such as a platelet coagulation-suppressive action, a smooth muscle relaxing action, a gastric acid secretion-suppressive action, a tunica mucosa ventriculi-protective action, an organ blood flow-increasing action and a tumor metastasis-suppressive action.
PGI.sub.2 synthase is present, particularly in large amounts, in vascular endothelial cells and vascular smooth muscle cells, and various production-stimulating substances promote production of PGI.sub.2.
From the studies heretofore done with regard to PGI.sub.2, it is known that substances such as arachidonic acid, bradykinin, histamine, serotonin, thrombin, calcium ionophore A23187, .alpha.-toxin, leukotriene C.sub.4 and D.sub.4, PDGF (platelet derived growth factor), HDL-cholesterol, human serum, nitroglycerin, angiotensin I and II and vitamin C have PGI.sub.2 production-stimulating action. The substances which promote PGI.sub.2 production are expected to become drugs useful for the diseases, for which the actions of PGI.sub.2, such as vasodilating action, bronchodilating action, gastric acid secretion-suppressive action and tumor metastasis-suppressive action, give the desired effects for improvement.
Hyperlipemia, arterioscrelosis and cerebral diseases (e.g., cerebral stroke, cerebral edema, cerebral softening, cerebral hemorrhage and cerebral infarction) are typical adult diseases on the rise in recent years along with the aging society, and the development of a pharmaceutical agent effective for the prevention and treatment of these diseases is desired.
Hyperlipemia is a condition accompanied by an abnormal increase in serum lipids, such as cholesterol, triglyceride and phospholipid. These lipids form, together with apoprotein, a macromolecular complex called lipoprotein in plasma. A lipoprotein is classified into five fractions of chylomicron, very low density lipoprotein (VLDL), low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and high density lipoprotein (HDL), according to the degree of density. Hyperlipemia is, for the convenience's sake, classified into the expression types of I-type (increase in chylomicron), IIa-type (increase in LDL), IIb-type (increase in LDL and VLDL), III-type (increase in B-VLDL), IV-type (increase in VLDL) and V-type (increase in chylomicron and VLDL), according to the kind of lipoprotein that has increased in the serum.
From clinical and practical points of view, it is considered beneficial to deal with hyperlipemia by subdividing the disease into hypercholesterolemia and hypertriglyceridemia. The fundamental treatment for the both diseases is alimentary therapy and appropriate exercises. When the symptom is not improved, drug therapy is introduced. The therapeutic agents currently in use for hyperlipemia are anion exchange resin, cholesterol synthesis inhibitor (HMG-CoA reductase inhibitor) and probucol for hypercholesterolemia; and clofibrate preparations and nicotinic acid preparations for hypertriglyceridemia.
Arteriosclerosis is a local disease caused by thickening or hardening of artery wall and triggered by hypertension, hyperlipemia and diabetes. About 15% of the adults in our country are considered to have hypercholesterolemia and there are many patients suffering from arteriosclerosis caused by hypercholesterolemia.
The dihydropyridine derivative (I) to be mentioned later has a calcium channel antagonistic action and is useful as a hypotenser, a periphery and cerebral vasodilator and a therapeutic agent for coronary artery disorders (therapeutic agent for angina pectoris) (Japanese Patent Unexamined Publication No. 225356/1988, U.S. Pat. No. 4,886,819, EP-A-257616).
The present inventors have conducted a wide variety of studies with regard to the dihydropyridine derivative (I) and found that said compound is extremely useful as a cerebral blood flow-increasing agent (Japanese Patent Unexamined Publication No. 62824/1990, EP-A-342577), a therapeutic agent for vasospasm (Japanese Patent Unexamined Publication No. 180826/1990, EP-A-379737) and a heart stimulant (Japanese Patent Unexamined Publication No. 235168/1992, EP-A-463407).